Secondary Logo

Journal Logo

Supplement Article

Propelling the Pediatric HIV Therapeutic Agenda With Science, Innovation, and Collaboration

Abrams, Elaine J. MD*; Ananworanich, Jintanat MD, PhD†,‡,§; Archary, Moherndran MBChB, PhD; Ngongondo, McNeil MBBS; Brouwers, Pim PhD#

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: August 15, 2018 - Volume 78 - Issue - p S32-S39
doi: 10.1097/QAI.0000000000001747
  • Open



Since the early 1990s, the public health response to the HIV epidemic has been driven by scientific discovery, innovation, and collaboration. Many landmark discoveries including the identification of the human immunodeficiency virus (HIV),1,2 the ability of the potent antiretrovirals (ARVs) to arrest viral replication,3 the effectiveness of ARVs to prevent vertical and horizontal transmission,4,5 and the health benefits of universal ARV treatment6–8 have transformed public policy and clinical practice. Furthermore, the timeline from development to regulatory approval for ARVs has been markedly accelerated, resulting in a new generation of highly potent, well-tolerated ARV agents that can be taken once daily, and revolutionizing the treatment landscape for adults living with HIV.9 The door has also been opened for long-acting ARV formulations, therapeutic vaccines, and immunotherapies to improve treatment and prevention and in the long term, to achieve epidemic control and HIV remission.10,11

The pediatric therapeutic agenda has generally lagged behind advances in the adult population, resulting in substantial delays in new medications, formulations, and approaches to treat HIV infection in infants, children, and adolescents.12–14 Historically, a number of well-described obstacles have thwarted drug development as well as intervention and pathogenesis research.12,13 The rapid growth and physical development that characterize the trajectory of childhood generally necessitates dose changes as well as unique formulations that can easily be administered to infants and young children. Traditionally, new drugs have been studied by age group, advancing from older to younger children, resulting in complex study designs with long timelines. Other impediments have included regulatory hurdles, cautious engagement and investment of pharmaceutical companies, limitations on blood volumes that can be obtained from small children, and ethical conundrums around participation of children and adolescents in research.12

Adding further complexity, unlike in adults where HIV infection can be diagnosed using a rapid antibody test, diagnosis in infants requires virologic testing (nucleic acid amplification test).15–17 Despite broad efforts to build laboratory and program capacity and infrastructure for early infant diagnosis (EID), less than half of all HIV-exposed infants globally received a virologic test by 2 months of age in 2016.18 Identification of older children and adolescents with HIV infection, where HIV antibody testing can be used, has also been suboptimal.19 Low rates of HIV diagnosis among children and adolescents are a major contributor to the poor rates of treatment coverage and virologic suppression. In 2016, only an estimated 43% of children less than 15 years of age living with HIV infection were receiving ARV treatment and ARV options remain limited.18 Despite an increased incidence of pretreatment nonnucleoside reverse transcriptase inhibitor resistance in infants, nevirapine with 2 nucleoside reverse transcriptase inhibitors remains the only available treatment regimen in many Sub-Saharan African countries.20–22 In 41 countries reporting on adolescent treatment, median antiretroviral therapy (ART) coverage was only 36% in 2016.23 Not surprisingly, viral suppression rates are lower among children and adolescents compared with adults. In the 2017 Swaziland HIV Incidence Measurement Survey, 91% of adults 25 years and older receiving ART were virally suppressed to <1000 copies per milliliter compared with 76% of 15–24-year-olds.24 In the Malawi Population HIV Incidence Measurement survey conducted in 2016, low rates of viral suppression on ART were found among children, 51.8% and 19.3%, respectively, among 5–9-year-olds and those younger than 4 years.25

Emerging evidence, however, suggests that there is renewed attention to the pediatric and adolescent HIV agenda as well as new opportunities to address many of the bottlenecks and challenges delaying progress.26,27 The development of a shared prioritized global research agenda for children and adolescents living with HIV was a critical step, underscoring the importance of research to achieve optimal outcomes for children and adolescents and to focus efforts of scientists, clinicians, policy makers, and the greater global community on the most pressing and relevant scientific questions.26–28 Momentum and change have been particularly evident in the area of therapeutics where science, innovation, and collaboration are propelling efforts to accelerate the availability of optimized ARV treatments for children.29 Of note, the prioritization exercise identified the study of the safety, efficacy, acceptability, pharmacokinetics, and optimal dosing of existing and new ARV drugs, formulations, and novel delivery systems as among the most important issues in the field.26

Spearheaded by the World Health Organization (WHO), diverse actors working in drug development, research, regulatory, and service delivery sectors are converging to address the urgent need to accelerate the availability of better ARVS for children from birth to 18 years of age. Several activities already in place include the Pediatric Antiretroviral Working Group (PAWG), a group of experts in pediatric and obstetric HIV prevention and treatment that provides key clinical, pharmacokinetic, and programmatic advice for new drug development. The PAWG develops dosing recommendations for existing and new ARV formulations, reviews pediatric investigational plans, provides technical input to pharmaceutical companies, and defines standards and new approaches to optimize clinical research on ARVs for children (Table 1).12 Researchers and research networks have already embraced the PAWG guidance, transforming approaches to studying ARV dosing and safety. The PAWG is currently developing a research toolkit to support and accelerate drug and formulation development for children. Pediatric antiretroviral drug optimization (PADO) is an annual review and prioritization of medium- and long-term priorities for the development of new ARV drugs and formulations for pediatric HIV treatment and prevention in the context of a public health approach.14 PADO produces a Pediatric ARV Drug Optimization List that guides pharmaceutical companies producing pediatric products ( Another important innovation for pediatrics has been the preparation of the Optimal Pediatric Formulary.30 Updated regularly, it establishes a minimum set of formulations to provide optimal ARV regimens for children. By informing country-level planning and procurement, the demand for products is consolidated across countries, reducing market fragmentation and allowing industry to produce a limited number of pediatric ARV formulations. Plans are also in development for a global accelerator for pediatric formulations (GAP-f), a collaborating platform supported by an innovative financing mechanism to promote a faster, more efficient, and more focused approach to pediatric formulation development and introduction.31 The GAP-f would coordinate upstream and downstream processes to accelerate priority drug development, availability, and uptake and would serve as a novel approach for drug development for other pediatric conditions (Fig. 1). Through collaboration across the private and public sectors, with researchers, clinicians, and community, processes are being established to ensure greater, more rapid availability of and access to more potent, robust, better-tolerated ARVs for children. The multistakeholder engagement is critical to promoting child-centered ethical research conduct.32 Social research to understand decision-making and perception of children and families in research could further inform best practices. Another high priority area of inquiry that arose from the research prioritization process is to increase our understanding of the short- and long-term outcomes of starting very early treatment in infants living with HIV: the impact on reservoir, remission, and cure.26 Historically, multitudes of challenges have complicated efforts to diagnosis and initiate ART close to the time of birth. New technologies, and innovative scientific approaches and collaborations have catalyzed new research efforts. Neurobehavioral abnormalities associated with HIV are common in children and require further research to inform preventive and rehabilitative interventions. The following case studies focus on infants and young children and initiatives to diagnose and effectively treatment newborns and infants. they will illustrate the critical role of basic science research and novel approaches to study design and implementation that are informing global efforts to end AIDS.

Innovations in Study Design to Accelerate Availability of Pediatric ARV Drugs
GAP-f. Adapted from Shortening the decade-long gap between adult and paediatric drug formulations: a new framework based on the HIV experience in low- and middle-income countries by Penazzato M, Lewis L, Watkins M, et al. (in press), 2017. HCW, health care worker; MOH, ministry of health.


Innovation Along the Diagnosis to Treatment Cascade

ART saves lives, and EID is the gateway into the pediatric treatment cascade. Despite recommendations from WHO to implement EID using nucleic acid amplification test at 4–6 weeks of life,15 only 9%–60% of infants exposed to HIV are tested before 2 months of age.33,34 This is primarily due to loss to follow-up between birth and first EID test.35 Moreover, it often takes over 4–10 weeks from obtaining samples to receiving results.36,37 Tragically, late treatment, illness, and deaths from HIV in infants remain common.

Routine HIV virologic testing at birth was added to existing diagnostic algorithms as a conditional recommendation in the 2016 WHO Guidelines.15 Its main goal is to lessen time to HIV diagnosis and ART initiation in infants infected with HIV in utero. Birth testing is particularly attractive for countries with a high rate of in-facility deliveries. Its cost-effectiveness and favorable outcomes were supported by mathematical modeling data from South Africa.38 To date, there are limited published data on the effects of birth EID on the infant testing and treatment cascade countries such as South Africa, Thailand, and Kenya that have adopted this strategy.

Linkage between testing and ART initiation, and retention in care are vital to achieving survival benefits of EID.35,39 Mobile health technology could improve linkage and retention in care. The HITSystem that was evaluated in Kenya provides a link between the laboratory, clinician, and caregiver. The system generates text messages to caregivers when EID results are available and prompts action, which has resulted in faster ART initiation and higher retention in care.40 MomConnect, a short-message service in South Africa, offers pregnancy advice and appointment reminders to pregnant women that could be extended to include EID reminders.41

Electronic health systems could be key in facilitating result notifications to health care workers and improving flow of information to key stakeholders including the ministries of health and implementation partners. Successfully piloted in South Africa, the national health laboratory service provides key stakeholders and clinical teams a weekly electronic list of HIV polymerase chain reaction test results performed per facility, district, or province. Infants diagnosed with HIV are actively traced by community health care workers and tracing teams based at a facility or district using a polymerase chain reaction registry that contains contact details of the caregiver.16 A similar web-based tracking system in Kenya has led to a shorter turnaround time from sample collection to patient notification.42 Next steps include continued evaluations of new technologies, and devising strategies for implementation in communities with high HIV burden, and limited access to telecommunication, electricity, and health services.

Very Early ART and HIV Cure

Children face a lifetime of ART and HIV stigma that makes finding a cure to HIV immensely important. In 2013, the case of the Mississippi baby propelled the interest of the public and the research community in early ART and HIV cure in children.43,44 Very early ART during the first 1–2 days of life in this infant subsequently led to undetectable viral load for 27 months after ART interruption at 18 months of age. The ability to maintain suppressed viremia in the absence of ART or HIV remission is also observed in adult cohorts,45 whose low HIV reservoir size after early treatment is a predominant feature.46

The Mississippi baby and the pediatric cure agenda in general provided an enormous impetus globally to identify and start treating infants as early as possible. Although only a few settings can engage in “cure” approaches, the approach shifted the timeline earlier along the cascade, drawing attention to the realities of delayed diagnosis, limited ARV options, and high rates of early morbidity and mortality in settings with high numbers of new infections.47 In the race to limit HIV reservoir seeding with early ART, the research and public health priorities merge. For example, in Thailand, researchers studying the HIV reservoirs and public health officers collaborated as part of the Active Case Management Network to increase the numbers of infants on ART and lower the age at ART initiation.48 Measures are being taken to strengthen EID programs and point of care virologic testing is gaining momentum,10,49–51 and applications now extend to monitoring of pediatric and adult HIV treatment.52,53 Over the past several years, new efforts have been made to find safe and potent ARVs with appropriate formulations and dosing for neonates and young infants54,55 ( NCT01828073; NCT 02778204).

Studies of HIV persistence under therapy have generated unique opportunities to incorporate science into pediatric therapeutic agenda that is important for the long-term goal of improving child health. When viral replication is inhibited early with ART, children display low levels of cell-associated HIV DNA and HIV RNA,56–59 shorter half-life of replication-competent virus from latently infected cells,57,60 and their noninduced proviral genomes are mostly defective.61 Young children have high frequencies of naive CD4+ T cells that are likely more resistant to HIV.62 Adolescents on ART since infancy with more than a decade of viral suppression are a unique population: their viral reservoirs continue to decay and only traces of HIV can be detected in their blood CD4+ T cells.63

Exciting data from an infant nonhuman primate model showed that simian/HIV immunodeficiency virus can be eradicated when combined broadly neutralizing antibodies were instituted within the first day or second day of infection.64 This is highly relevant to the pediatric HIV cure agenda with known timing of infection affording immediate HIV diagnosis and treatment. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) is investigating broadly neutralizing antibody given in addition to ART to HIV-exposed (P1112, NCT02256631) and newly HIV-infected infants (P2008, NCT03208231). The global Early-treated Perinatally HIV-infected individuals: Improving Children's Actual Life with Novel Immunotherapeutic Strategies (EPIICAL) network is dedicated to advancing therapies for HIV cure in the early treated pediatric population.65 Unlike adults, children have an active thymus and immune regeneration ability that is key to mounting responses to vaccines. Vaccine responses in children can be as good or better compared with adults for both non-HIV66 and HIV vaccines.67–70 HIV-exposed uninfected infants who received ALVAC (canarypox vector containing env, gag, pol)/AIDSVAX (engineered gp120 protein) had 22-fold higher levels and longer durability of the correlate for HIV protection, anti V1V2 IgG, than adults in the RV144 Thai trial.69 Perinatally, HIV-infected children mounted higher HIV-specific immune responses to new epitopes after HIVIS DNA vaccine (7 plasmids of env, gag, Rev, and RT) compared with adults given the same vaccine.67 Together, these data support the notion that early treated children may be more likely to respond to immunotherapeutics for cure.71 Pediatric HIV cure research is poised to critically contribute to the global research efforts to curing HIV and to further drive the pediatric agenda to optimize treatments for the youngest children.

ARTs for Neonates and Young Infants

Emerging evidence of the potential benefits of very early treatment of HIV-infected neonates has propelled efforts to expand therapeutic options for infants. Currently, there are only 5 ARVs with appropriate formulations, dosing, and safety data to recommend their use in full-term neonates [zidovudine, lamivudine, nevirapine, lopinavir/ritonavir (at 2 weeks of age), and raltegravir].72,73 The dosage and therapeutic use of nevirapine in newborns is investigational. However, important strides are being made to accelerate the development, study, and availability of the most potent ARVs to treat young babies.12

Historically, there has been little impetus to develop ARVs for newborn treatment. With routine infant diagnosis scheduled for 6 weeks of life, most infants who were successfully diagnosed and engaged in care did not begin ART until well beyond the second month of life. Furthermore, distinct aspects of early life make both the development and study of drugs substantially more complex compared with adults and older children.72–74 The first months of life are a dynamic developmental period characterized by rapid physiologic changes that influence drug metabolism, and in turn, dosing and toxicities. High rates of prematurity, low birth weight, and concomitant health conditions among infants born to women living with HIV infection add another set of considerations when determining dosing and safety of new agents.75,76 The need for formulations other than liquids that are safe, acceptable, and feasible for use in low- and middle-income settings has further delayed access to new medications for infants.

The landscape of early infant treatment is slowly shifting, accelerated by collaboration among key stakeholders as well as the application of recommended innovations to drug development and study design.12 For example, after a long period of development, lopinavir/ritonavir pellets, an alternative to the poorly palatable, heat-sensitive liquid formulation, were approved for children older than 3 months.77,78 Dosing and acceptability of the new formulation were determined in the CHAPAS-3 study.77,78 The LIVING study is now evaluating the effectiveness of the pellet formulation in combination with zidovudine and lamivudine fixed-dose combination tablets under routine conditions in Sub-Saharan Africa in infants and young children who cannot swallow tablets ( NCT02346487).79 In lieu of a separate study for children younger than 3 months, LIVING has been designed to include children starting treatment at birth to obtain safety and acceptability data for this age group. A lopinavir/ritonavir granule formulation and a four-in-one (lopinavir/ritonavir with abacavir and lamivudine) granule/powder product are anticipated to be available in the near future.”

Scientific networks and investigators have embraced the weight-band dosing approach in lieu of the age-range dosing approach traditionally used in pediatric pharmacokinetic studies. Investigators are now using sophisticated modeling and simulation techniques using data from older children and adults to inform dosing strategies for neonates and infants.72,73 Washout pharmacokinetic studies, measuring newborn blood levels during the first days to weeks of life of transplacentally transferred maternal ARVs, have also given insight into the behavior of specific agents during this period of rapid physiologic change. Raltegravir, available in a chewable tablet and a granule formulation, was recently approved for use in full-term neonates and is an excellent example of optimizing data sources to inform pediatric dosing.80 Investigators used pharmacokinetic data from older children and adults, a small phase I trial in newborns, and maternal washout studies to select a daily dosing regimen that was then tested and ultimately approved for very early treatment.81–83 Studies are underway to extend dosing to low birth weight babies. The development plan for dolutegravir is following a similar pathway, maximizing data sources, modeling pharmacokinetics and dosing, and testing doses in small mini-cohorts of children ( NCT01302847).84,85 In parallel, efficacy and additional dosing and safety data are being studied in the ODYSSEY trial ( NCT02259127). These combined efforts should lead to more rapid approval and availability of dolutegravir for all children including neonates.

HIV, ART, and Early Brain Development

Brain development begins during the first trimester and continues into early adulthood. The immaturity of the central nervous system (CNS) through adolescence makes it vulnerable to insults from HIV and its treatments, and places infants and children with HIV at particular risk of damage to developing structures and functions. Thus, timing of infant HIV infection (in utero, intrapartum, postnatal),86 maternal health status,87 and effective ART initiation are major determinants of frequency and severity of abnormalities. Although severe CNS effects from HIV (ie, encephalopathy) are uncommon since the introduction of earlier ART, more subtle neurobehavioral abnormalities remain in some children and may be related to host,88 viral,89 and treatment factors.90 There may be a critical window of opportunity when abnormalities can be prevented by early ART,91,92 but the precise timing is under investigation. The effects of early therapy on the CNS are being studied and include CNS penetration of ART drugs on neurologic outcome and use of comprehensive neurobehavioral assessments.93

Studies are underway to better characterize subtle abnormalities94 that are also observed in virologically suppressed children, as well as to understand their potential impact on daily life.95 These abnormalities may be static because of delayed or suboptimal treatment or progressive because of ongoing immunologic or virologic processes.96 Some static neurologic deficits may only manifest at an older age as a possible consequence of “growing into a deficit.”97,98 An example of the latter is mathematics ability, compromised at an early age, but evident only with maturity and reliance on such ability. Neurobehavioral HIV studies benefit from recent developments in behavioral and brain-imaging assessments. Brain-imaging studies with higher specificity and resolution have identified abnormalities in specific cerebral structures99,100 that are related to specific neuropsychological deficits. Similarly, computerized neurocognitive testing may provide more standardized and reliable administration and results, and improve implementation in a less resourced environment.101 Longitudinal neurobehavior and neuroimaging control data from children in the general population are being generated.102,103 In addition, pediatric HIV research networks, both treatment-oriented such as the IMPAACT104 and PENTA-ID105 as well as cohort studies such as the Pediatric HIV/AIDS Cohort Study (PHACS)106 and CIPHER,107 are addressing HIV-associated neurobehavioral and psychiatric issues.

HIV-exposed uninfected children born to mothers on ART during and after pregnancy form a growing population impacted by HIV. Exposures to HIV and perinatal ART have been related to potential acute as well as late neurobehavioral sequelae.98,108 Timing of exposure to a specific ARV agent and maternal immunologic and virologic status during pregnancy may be contributing factors.109 However, longer follow-up is needed particularly for newer ARVs. Moreover, available evidence has not unambiguously linked currently available ARVs to adverse clinical outcomes.

Although much of the earlier work characterized the neurobehavioral abnormalities, current research has focused on the prevention and rehabilitation of the deficits.110 Besides very early ART,91 ability-based and parent-based interventions may ameliorate some of the neurobehavioral deficits.111–113 Even as effective ART is available to prevent and treat infant HIV infection, long-term outcomes with respect to brain structure and function remain a concern and require continued monitoring and tailored preventive and rehabilitative interventions.


Scientific discovery, innovation, and collaboration are key drivers propelling efforts to improve diagnostics, optimize treatments, and enhance the health outcomes of children living with HIV infection. Scientists, policy makers, implementers, and industry have aligned to advance the pediatric therapeutic agenda and results are paying off. Key examples are the prioritized global research agenda, PAWG guidance, PADO prioritization list, and GAP-f. New medications and formulations for children are under development and a number of new ARVs are becoming available at a more rapid pace than ever before. Interest in very early treatment to achieve a cure and to prevent CNS disease have focused attention on treatment of neonates and given new urgency to efforts to improve the EID cascade and have potent, safe, and well-tolerated ARV regimens for youngest children.


The authors thank Oratai Butterworth for her help in formatting the manuscript.


1. Barre-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983;220:868–871.
2. Gallo RC, Sarin PS, Gelmann EP, et al. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science. 1983;220:865–867.
3. Markowitz M, Saag M, Powderly WG, et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. New Engl J Med. 1995;333:1534–1539.
4. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. New Engl J Med. 1994;331:1173–1180.
5. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. New Engl J Med. 2011;365:493–505.
6. Cotton MF, Violari A, Otwombe K, et al. Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial. Lancet. 2013;382:1555–1563.
7. Lundgren JD, Babiker AG, Gordin F, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. New Engl J Med. 2015;373:795–807.
8. Danel C, Moh R, Gabillard D, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. New Engl J Med. 2015;373:808–822.
9. Flexner CW, Clayden P, Venter WDF. Why a universal antiretroviral regimen? Curr Opin HIV AIDS. 2017;12:315–317.
10. Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017;390:1499–1510.
11. Byrareddy SN, Arthos J, Cicala C, et al. Sustained virologic control in SIV+ macaques after antiretroviral and alpha4beta7 antibody therapy. Science. 2016;354:197–202.
12. Penazzato M, Gnanashanmugam D, Rojo P, et al. Optimizing research to speed up availability of pediatric antiretroviral drugs and formulations. Clin Infect Dis. 2017;64:1597–1603.
13. Penazzato M, Lee J, Capparelli E, et al. Optimizing drugs to reach treatment targets for children and adolescents living with HIV. J Int AIDS Soc. 2015;18(suppl 6):20270.
14. Penazzato M, Palladino C, Sugandhi N. Prioritizing the most needed formulations to accelerate paediatric antiretroviral therapy scale-up. Curr Opin HIV AIDS. 2017;12:369–376.
15. World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treatment and Prevention HIV Infection: Recommendations for a Public Health Approach. 2nd ed. World Health Organization, Geneva Switzerland: 2016. Available at: Accessed December 20, 2017.
16. Celletti F, Sherman G, Mazanderani AH. Early infant diagnosis of HIV: review of current and innovative practices. Curr Opin HIV AIDS. 2017;12:112–116.
17. Dunning L, Francke JA, Mallampati D, et al. The value of confirmatory testing in early infant HIV diagnosis programmes in South Africa: a cost-effectiveness analysis. PLoS Med. 2017;14:e1002446.
18. Joint United Nations Programme on HIV/AIDS. Ending AIDS. Progress towards the 90-90-90 targets. Global AIDS update | 2017. Available at: Accessed December 20, 2017.
19. PHIA project. Available at: Accessed December 20, 2017.
20. Jordan MR, Penazzato M, Cournil A, et al. Human immunodeficiency virus (HIV) drug resistance in African infants and young children newly diagnosed with HIV: a multicountry analysis. Clin Infect Dis. 2017;65:2018–2025.
21. Kityo C, Sigaloff KC, Sonia Boender T, et al. HIV drug resistance among children initiating first-line antiretroviral treatment in Uganda. AIDS Res Hum Retroviruses. 2016;32:628–635.
22. Kuhn L, Hunt G, Technau KG, et al. Drug resistance among newly diagnosed HIV-infected children in the era of more efficacious antiretroviral prophylaxis. AIDS. 2014;28:1673–1678.
23. UNICEF. Monitoring the situation of children and women. HIV/AIDS statistical tables. 2017. Available at: Accessed December 20, 2017.
24. Nkambule R, Nuwagaba-Biribonwoha H, Mnisi Z, et al. Substantial progress in confronting the HIV epidemic in Swaziland: first evidence of national impact. Paper presented at: 9th IAS Conference on HIV Science; July 23–26, 2017; Paris, France.
25. Jonnalagadda S, Bello G, Suzue S, et al. Children living with HIV in Malawi: first survey-based measurement of national paediatric HIV prevalence and viral suppression. Paper presented at: 9th IAS Conference on HIV Science; July 23–26, 2017; Paris, France.
26. Penazzato M, Amzel A, Abrams EJ, et al. Pediatric treatment scale-up: the unfinished agenda of the global plan. J Acquir Immune Defic Syndr. 2017;75(suppl 1):S59–S65.
27. Mark D, Armstrong A, Andrade C, et al. HIV treatment and care services for adolescents: a situational analysis of 218 facilities in 23 sub-Saharan African countries. J Int AIDS Soc. 2017;20(suppl 3):21591.
28. World Health Organization, CIPHER, International AIDS Society. A global research agenda for paediatric HIV. Research for an AIDS free generation. Available at: Accessed December 20, 2017.
29. World Health Organization. Action plan for scaling up early diagnosis and treatment of children and adolescents. Pontifical Academy of Sciences, Vatican City, November 17, 2017. Available at: Accessed December 20, 2017.
30. World Health Organization, IATT, UNICEF. Policy Brief, IATT paediatric ARV formulary and limited-use list: 2016 update. Available at: Accessed December 20, 2017.
31. Mooney M, McWeeney S, Sekaly RP. Systems immunogenetics of vaccines. Semin Immunol. 2013;25:124–129.
32. Scanlon ML, MacNaughton G, Sprague C. Neglected population, neglected right: children living with HIV and the right to science. Health Hum Rights. 2017;19:169–181.
33. UNICEF. For Every Child, End AIDS: Seventh Stocktaking Report 2016. 2016. Available at: Accessed November 21, 2017.
34. UNAIDS. Global HIV Statistics—July 2017 UNAIDS. Fact Sheet. 2017. Available at: Accessed November 21, 2017.
35. Jean-Philippe P, Spiegel H, Gnanashanmugam D, et al. HIV birth testing and linkage to care for HIV-infected infants. AIDS. 2017;31:1797–1807.
36. Ferrand RA. Gaps in the early infant diagnosis cascade in a high HIV prevalence setting. Public Health Action. 2017;7:78.
37. Phiri NA, Lee HY, Chilenga L, et al. Early infant diagnosis and outcomes in HIV-exposed infants at a central and a district hospital, Northern Malawi. Public Health Action. 2017;7:83–89.
38. Francke JA, Penazzato M, Hou T, et al. Clinical impact and cost-effectiveness of diagnosing HIV infection during early infancy in South Africa: test timing and frequency. J Infect Dis. 2016;214:1319–1328.
39. Bobat R, Archary M, Lawler M. An update on the HIV treatment cascade in children and adolescents. Curr Opin HIV AIDS. 2015;10:411–419.
40. Finocchario-Kessler S, Goggin K, Khamadi S, et al. Improving early infant HIV diagnosis in Kenya: study protocol of a cluster-randomized efficacy trial of the HITSystem. Implement Sci. 2015;10:96.
41. MomConnect. Available at: Accessed November 21, 2017.
42. Finocchario-Kessler S, Odera I, Okoth V, et al. Lessons learned from implementing the HIV infant tracking system (HITSystem): a web-based intervention to improve early infant diagnosis in Kenya. Healthc (Amst). 2015;3:190–195.
43. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. New Engl J Med. 2013;369:1828–1835.
44. Luzuriaga K, Gay H, Ziemniak C, et al. Viremic relapse after HIV-1 remission in a perinatally infected child. New Engl J Med. 2015;372:786–788.
45. Saez-Cirion A, Bacchus C, Hocqueloux L, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9:e1003211.
46. Williams JP, Hurst J, Stohr W, et al. HIV-1 DNA predicts disease progression and post-treatment virological control. Elife. 2014;3:e03821.
47. Luzuriaga K, Mofenson LM. Eliminating pediatric HIV-1 infection. New Engl J Med. 2016;375:193–194.
48. Lolekha R, Pavaputanondh P, Puthanakit T, et al. Implementation of an active case management network to identify HIV-infected infants and accelerate the initiation of antiretroviral therapy, Thailand 2015. Paper presented at: The 21st International AIDS Conference; July 18–22, 2016; Durban, South Africa.
49. Technau KG, Kuhn L, Coovadia A, et al. Xpert HIV-1 point-of-care test for neonatal diagnosis of HIV in the birth testing programme of a maternity hospital: a field evaluation study. Lancet HIV. 2017;4:e442–e448.
50. Meggi B, Bollinger T, Mabunda N, et al. Point-of-care p24 infant testing for HIV may increase patient identification despite low sensitivity. PLoS One. 2017;12:e0169497.
51. Frank SC, Cohn J, Dunning L, et al. The clinical impact and cost-effectiveness of incorporating point-of-care (POC) assays into early infant HIV diagnosis (EID) programs at 6 weeks of age in Zimbabwe: a model-based analysis. Paper presented at: 9th IAS Conference on HIV Science; July 23–26, 2017; Paris, France.
52. Fidler S, Lewis H, Meyerowitz J, et al. A pilot evaluation of whole blood finger-prick sampling for point-of-care HIV viral load measurement: the UNICORN study. Sci Rep. 2017;7:13658.
53. Dorward J, Garrett N, Quame-Amaglo J, et al. Protocol for a randomised controlled implementation trial of point-of-care viral load testing and task shifting: the Simplifying HIV TREAtment and Monitoring (STREAM) study. BMJ Open. 2017;7:e017507.
54. Strehlau R, Donati AP, Arce PM, et al. PRINCE-1: safety and efficacy of atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naive and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.
55. Rizk ML, Du L, Bennetto-Hood C, et al. Population pharmacokinetic analysis of raltegravir pediatric formulations in HIV-infected children 4 weeks to 18 years of age. J Clin Pharmacol. 2015;55:748–756.
56. Ananworanich J, Puthanakit T, Suntarattiwong P, et al. Reduced markers of HIV persistence and restricted HIV-specific immune responses after early antiretroviral therapy in children. AIDS. 2014;28:1015–1020.
57. van Zyl GU, Bedison MA, van Rensburg AJ, et al. Early antiretroviral therapy in South African children reduces HIV-1-infected cells and cell-associated HIV-1 RNA in blood mononuclear cells. J Infect Dis. 2015;212:39–43.
58. Martinez-Bonet M, Puertas MC, Fortuny C, et al. Establishment and replenishment of the viral reservoir in perinatally HIV-1-infected children initiating very early antiretroviral therapy. Clin Infect Dis. 2015;61:1169–1178.
59. Persaud D, Patel K, Karalius B, et al. Influence of age at virologic control on peripheral blood human immunodeficiency virus reservoir size and serostatus in perinatally infected adolescents. JAMA Pediatr. 2014;168:1138–1146.
60. Persaud D, Ray SC, Kajdas J, et al. Slow human immunodeficiency virus type 1 evolution in viral reservoirs in infants treated with effective antiretroviral therapy. AIDS Res Hum Retroviruses. 2007;23:381–390.
61. Rainwater-Lovett K, Ziemniak C, Watson D, et al. Paucity of intact non-induced provirus with early, long-term antiretroviral therapy of perinatal HIV infection. PLoS One. 2017;12:e0170548.
62. Chomont N, El-Far M, Ancuta P, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15:893–900.
63. Luzuriaga K, Tabak B, Garber M, et al. HIV type 1 (HIV-1) proviral reservoirs decay continuously under sustained virologic control in HIV-1-infected children who received early treatment. J Infect Dis. 2014;210:1529–1538.
64. Hessell AJ, Jaworski JP, Epson E, et al. Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques. Nat Med. 2016;22:362–368.
65. Palma P, Foster C, Rojo P, et al. The EPIICAL project: an emerging global collaboration to investigate immunotherapeutic strategies in HIV-infected children. J Virus Erad. 2015;1:134–139.
66. Martinez DR, Permar SR, Fouda GG. Contrasting adult and infant immune responses to HIV infection and vaccination. Clin Vaccin Immunol. 2015;23:84–94.
67. Palma P, Gudmundsdotter L, Finocchi A, et al. Immunotherapy with an HIV-DNA vaccine in children and adults. Vaccines. 2014;2:563–580.
68. Cunningham CK, Wara DW, Kang M, et al. Safety of 2 recombinant human immunodeficiency virus type 1 (HIV-1) envelope vaccines in neonates born to HIV-1-infected women. Clin Infect Dis. 2001;32:801–807.
69. Fouda GG, Cunningham CK, McFarland EJ, et al. Infant HIV type 1 gp120 vaccination elicits robust and durable anti-V1V2 immunoglobulin G responses and only rare envelope-specific immunoglobulin A responses. J Infect Dis. 2015;211:508–517.
70. McGuire EP, Fong Y, Toote C, et al. HIV exposed infants vaccinated with a MF59/rgp120 vaccine have higher magnitude anti-V1V2 IgG responses than adults immunized with the same vaccine. J Virol. 2017;92:pii: e01070–17.
71. Klein N, Palma P, Luzuriaga K, et al. Early antiretroviral therapy in children perinatally infected with HIV: a unique opportunity to implement immunotherapeutic approaches to prolong viral remission. Lancet Infect Dis. 2015;15:1108–1114.
72. Clarke DF, Penazzato M, Capparelli E, et al. Prevention and treatment of HIV infection in neonates: evidence base for existing WHO dosing recommendations and implementation considerations. Expert Rev Clin Pharmacol. 2018;11:83–93.
73. Cotton MF, Holgate S, Nelson A, et al. The last and first frontier–emerging challenges for HIV treatment and prevention in the first week of life with emphasis on premature and low birth weight infants. J Int AIDS Soc. 2015;18(suppl 6):20271.
74. Smits A, Annaert P, Allegaert K. Drug disposition and clinical practice in neonates: cross talk between developmental physiology and pharmacology. Int J Pharm. 2013;452:8–13.
75. Uthman OA, Nachega JB, Anderson J, et al. Timing of initiation of antiretroviral therapy and adverse pregnancy outcomes: a systematic review and meta-analysis. Lancet HIV. 2017;4:e21–e30.
76. Slogrove AL, Clayden P, Abrams EJ. Toward a universal antiretroviral regimen: special considerations of pregnancy and breast feeding. Curr Opin HIV AIDS. 2017;12:359–368.
77. Musiime V, Fillekes Q, Kekitiinwa A, et al. The pharmacokinetics and acceptability of lopinavir/ritonavir minitab sprinkles, tablets, and syrups in African HIV-infected children. J Acquir Immune Defic Syndr. 2014;66:148–154.
78. Kekitiinwa A, Musiime V, Thomason MJ, et al. Acceptability of lopinavir/r pellets (minitabs), tablets and syrups in HIV-infected children. Antivir Ther. 2016;21:579–585.
79. Salami O, Kekitiinwa A, Wamalwa D, et al. Prospective study of lopinavir based ART for HIV-infected children globally (LIVING study): Interim 48-week effectiveness and safety results. Paper presented at: 19th ICASA Conference December 4–9, 2017; Abidjan, Côte d'Ivoire.
80. Fukazawa Y, Park H, Cameron MJ, et al. Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines. Nat Med. 2012;18:1673–1681.
81. Lommerse J, Clarke D, Chain A, et al. Raltegravir PK in neonates—an adaptive trial design to define an appropriate regimen for neonates from birth to 6 weeks of age. Paper presented at: American Conference on Pharmacometrics (ACoP); October 23–26, 2016; Bellevue, Washington.
82. Clarke DF, Wong RJ, Wenning L, et al. Raltegravir in vitro effect on bilirubin binding. Pediatr Infect Dis J. 2013;32:978–980.
83. Clarke DF, Acosta EP, Rizk ML, et al. Raltegravir pharmacokinetics in neonates following maternal dosing. J Acquir Immune Defic Syndr. 2014;67:310–315.
84. Viani RM, Alvero C, Fenton T, et al. Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV-1 infected adolescents: forty-eight-week results from IMPAACT P1093. Pediatr Infect Dis J. 2015;34:1207–1213.
85. Wiznia A, Alvero C, Fenton T, et al. IMPAACT 1093: dolutegravir in 6- to 12-year-old HIV-infected children: 48-week results. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22–25, 2016; Boston, MA.
86. Smith R, Malee K, Charurat M, et al. Timing of perinatal human immunodeficiency virus type 1 infection and rate of neurodevelopment. The Women and Infant Transmission Study Group. Pediatr Infect Dis J. 2000;19:862–871.
87. Smith R, Chernoff M, Williams PL, et al. Impact of HIV severity on cognitive and adaptive functioning during childhood and adolescence. Pediatr Infect Dis J. 2012;31:592–598.
88. Ananworanich J, Bunupuradah T, Apornpong T, et al. Association between lymphocyte and monocyte subsets and cognition in children with HIV. AIDS Res Ther. 2014;11:7.
89. Bangirana P, Ruel TD, Boivin MJ, et al. Absence of neurocognitive disadvantage associated with paediatric HIV subtype A infection in children on antiretroviral therapy. J Int AIDS Soc. 2017;20:e25015.
90. Mbugua KK, Holmes MJ, Cotton MF, et al. HIV-associated CD4+/CD8+ depletion in infancy is associated with neurometabolic reductions in the basal ganglia at age 5 years despite early antiretroviral therapy. AIDS. 2016;30:1353–1362.
91. Laughton B, Cornell M, Grove D, et al. Early antiretroviral therapy improves neurodevelopmental outcomes in infants. AIDS. 2012;26:1685–1690.
92. Puthanakit T, Ananworanich J, Vonthanak S, et al. Cognitive function and neurodevelopmental outcomes in HIV-infected children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study. Pediatr Infect Dis J. 2013;32:501–508.
93. Boivin MJ, Barlow-Mosha L, Chernoff MC, et al. Neuropsychological performance in African children with HIV enrolled in a multisite antiretroviral clinical trial. AIDS. 2018;32:189–204.
94. Llorente AM, Brouwers P, Leighty R, et al. An analysis of select emerging executive skills in perinatally HIV-1-infected children. Appl Neuropsychol Child. 2014;3:10–25.
95. Garvie PA, Zeldow B, Malee K, et al. Discordance of cognitive and academic achievement outcomes in youth with perinatal HIV exposure. Pediatr Infect Dis J. 2014;33:e232–e238.
96. Innes S, van Toorn R, Otwombe K, et al. Late-onset HIV encephalopathy in children with long-standing virologic suppression followed by slow spontaneous recovery despite no change in antiretroviral therapy: 4 case reports. Pediatr Infect Dis J. 2017;36:e264–e267.
97. Aarsen FK, Paquier PF, Arts WF, et al. Cognitive deficits and predictors 3 years after diagnosis of a pilocytic astrocytoma in childhood. J Clin Oncol. 2009;27:3526–3532.
98. Smith ML, Puka K, Sehra R, et al. Longitudinal development of cognitive, visuomotor and adaptive behavior skills in HIV uninfected children, aged 3-5 years of age, exposed pre- and perinatally to anti-retroviral medications. AIDS Care. 2017;29:1302–1308.
99. Randall SR, Warton CMR, Holmes MJ, et al. Larger subcortical gray matter structures and smaller corpora callosa at age 5 years in HIV infected children on early ART. Front Neuroanat. 2017;11:95.
100. Hoare J, Fouche JP, Phillips N, et al. Clinical associations of white matter damage in cART-treated HIV-positive children in South Africa. J Neurovirol. 2015;21:120–128.
101. Bangirana P, Sikorskii A, Giordani B, et al. Validation of the CogState battery for rapid neurocognitive assessment in Ugandan school age children. Child Adolesc Psychiatry Ment Health. 2015;9:38.
102. Jernigan TL, Brown TT, Hagler DJ Jr, et al. The pediatric imaging, neurocognition, and genetics (PING) data repository. Neuroimage. 2016;124:1149–1154.
103. Yue FY, Cohen JC, Ho M, et al. HIV-specific granzyme B, but not interferon-gamma secreting T Cells are associated with reduced viral reservoirs in early HIV infection. J Virol. 2017;91:pii: e02233–16.
104. Lee WS, Richard J, Lichtfuss M, et al. Antibody-dependent cellular cytotoxicity against reactivated HIV-1-infected cells. J Virol. 2015;90:2021–2030.
105. Kang W, Zhu W, Li Y, et al. Analysis of HIV-1c-specific CTL responses with HIV-1 reservoir size and forms. Viral Immunol. 2016;29:184–191.
106. Van Dyke RB, Chadwick EG, Hazra R, et al. The PHACS SMARTT study: assessment of the safety of in utero exposure to antiretroviral drugs. Front Immunol. 2016;7:199.
107. Ndhlovu ZM, Stampouloglou E, Cesa K, et al. The breadth of expandable memory CD8+ T cells inversely correlates with residual viral loads in HIV elite controllers. J Virol. 2015;89:10735–10747.
108. Spaulding AB, Yu Q, Civitello L, et al. Neurologic outcomes in HIV-exposed/uninfected infants exposed to antiretroviral drugs during pregnancy in Latin America and the Caribbean. AIDS Res Hum Retroviruses. 2016;32:349–356.
109. Himes SK, Huo Y, Siberry GK, et al. Meconium atazanavir concentrations and early language outcomes in HIV-exposed uninfected infants with prenatal atazanavir exposure. J Acquir Immune Defic Syndr. 2015;69:178–186.
110. Boivin MJ, Ruisenor-Escudero H, Familiar-Lopez I. CNS impact of perinatal HIV infection and early treatment: the need for behavioral rehabilitative interventions along with medical treatment and care. Curr HIV/AIDS Rep. 2016;13:318–327.
111. Bass JK, Opoka R, Familiar I, et al. Randomized controlled trial of caregiver training for HIV-infected child neurodevelopment and caregiver well being. AIDS. 2017;31:1877–1883.
112. Pardo G, Saisaengjan C, Gopalan P, et al. Cultural adaptation of an evidence-informed Psychosocial intervention to address the needs of PHIV+ youth in Thailand. Glob Soc Welfare. 2017;4:209–218.
113. Boivin MJ, Nakasujja N, Sikorskii A, et al. A randomized controlled trial to evaluate if computerized cognitive rehabilitation improves neurocognition in Ugandan children with HIV. AIDS Res Hum Retroviruses. 2016;32:743–755.

very early antiretroviral treatment; pediatric antiretroviral drugs

Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc.